(1) We analyzed parasite recrudescence rates following dihydroartemisinin-piperaquine treatment in patients with falciparum malaria in three Cambodian provinces, and found that parasites that failed treatment were resistant to both artemisinin and piperaquine. (2) In a genome-wide association study of in-vitro piperaquine responses, we identified two new molecular markers of piperaquine resistance - a nonsynonymous single-nucleotide polymorphism in an exonuclease gene and an amplification of the plasmepsin II-III genes - that predict increased risk of dihydroartemisinin-piperaquine failure in Cambodia. (3) We analysed a clinical trial of artesunate-mefloquine for the treatment of dihydroartemisinin-piperaquine failures and found it to be 100% effective. This finding supports further clinical trials to investigate whether the triple combination dihydroartemisinin-piperaquine-mefloquine is safe, tolerated, and effective in treating falciparum malaria in Cambodia, and led to the World Health Organization's recent decision to reinstate artesunate-mefloquine as the first-line combination treatment in 10 Cambodian provinces where dihydroartemisinin-piperaquine failures have been observed. (4) We found that artemisinin-resistant parasites from Cambodia infect diverse anopheline vectors of Southeast Asia and Africa, suggesting that mosquito-parasite incompatibility presents no strong barrier to the global spread of these parasites. (5) We found that cow-baited tents are highly efficient in capturing Anopheles mosquito vectors. Using this method in areas where malaria transmission is occurring in Cambodia, we identified 36 Anopheles species, half of which we found to be transmitting Plasmodium parasites.